Long‐term results of an ultra low‐dose cytarabine‐based regimen for the treatment of acute megakaryoblastic leukaemia in children with Down syndrome

Al-Ahmari, Ali; Shah, Niketa C.; Sung, Lillian; Zipursky, Alvin; Hitzler, Johann

doi:10.1111/j.1365-2141.2006.06097.x

Cited by 51 publications

(28 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Different cooperative groups are considering further reduction of treatment intensity for children with DS-AML in view of toxicity concerns and the unique enhanced sensitivity of DS-AML cells to cytarabine [7,8,29]. However, in light of the low infectious morbidity and mortality in our study, further treatment intensity reduction might not provide additional safety advantages but may compromise event-free survival rates in children with DS-AML.…”

Section: Discussionmentioning

confidence: 87%

Infections in children with down syndrome and acute myeloid leukemia: a report from the Canadian infections in AML research group

Tran

Mitchell

Dix

et al. 2013

Infect Agents Cancer

Self Cite

View full text Add to dashboard Cite

BackgroundChildren with Down syndrome (DS) are at high risk of infectious toxicity when treated with acute lymphoblastic leukemia chemotherapy protocols optimized in children without DS. Our objective was to determine if children with DS and acute myeloid leukemia (AML) have a different risk of infection when treated with chemotherapy protocols developed for children with DS compared to AML treatment protocols developed for children without DS.MethodsWe conducted a retrospective, population-based cohort study that included DS children ≤ 18 years of age with de novo, non-M3 AML diagnosed between January 1995 and December 2004, and treated at 15 Canadian centers. Patients were monitored for infection from initiation of AML treatment until recovery from the last cycle of chemotherapy, conditioning for hematopoietic stem cell transplantation, relapse, persistent disease or death (whichever occurred first). Trained research associates abstracted all information from each site.ResultsThere were 31 children with DS included; median age was 1.7 (range 0.1-11.1) years. Eleven were treated according to a DS-specific protocol while 20 were treated with non-DS specific protocols. A total of 157 courses of chemotherapy were delivered. Microbiologically documented sterile site infection occurred in 11.9% and 14.3% of DS-specific and non-DS specific AML treatment courses respectively. Sepsis was rare and there were no infection-related deaths. In multiple regression, treatment with a DS-specific protocol was independently associated with a reduction in microbiologically documented sterile site infection (adjusted odds ratio (OR) 0.65, 95% confidence interval (CI) 0.42-0.99; P = 0.044), and clinically documented infection (adjusted OR 0.36, 95% CI 0.14-0.91; P = 0.031) but not bacteremia (adjusted OR 0.73, 95% CI 0.44-1.22; P = 0.231).ConclusionsOur study suggests that children with DS do not experience excessive infectious toxicity during treatment for AML compared to children without DS. Incorporation of DS-specific AML treatment protocols is associated with a more favorable infection profile for children with DS-AML.

show abstract

Section: Discussionmentioning

confidence: 87%

Infections in children with down syndrome and acute myeloid leukemia: a report from the Canadian infections in AML research group

Tran

Mitchell

Dix

et al. 2013

Infect Agents Cancer

Self Cite

View full text Add to dashboard Cite

show abstract

“…Whereas in most European and North American trials for ML-DS courses with highdose cytarabine (3 g/m 2 per day) are applied, [9][10][11][12] Japanese studies (Japan Pediatric Leukemia/Lymphoma Study Group [JPLSG] AML D05) obtained excellent results (3-year OS: 88% 6 4% 3-year EFS: 83% 6 4%) and low TRM (1.4%) using standard-dose cytarabine (100 mg/m 2 per day) only. 15 Together with the results of the Toronto group that used a low-dose cytarabine-based regimen, 13,32 which contained no anthracyclines and no etoposide, these data indicate that subgroups of patients with ML-DS can be cured even with much lower doses than in the current ML-DS 2006 trial. But the identification of clear prognostic factors that would predict which patients are at risk of relapse and need intense therapy remained elusive.…”

Section: Discussionmentioning

confidence: 95%

Therapy reduction in patients with Down syndrome and myeloid leukemia: the international ML-DS 2006 trial

Rasche

Zimmermann

et al. 2017

Blood

View full text Add to dashboard Cite

Key Points• Reducing therapy intensity in the ML-DS 2006 trial did not impair the excellent prognosis in ML-DS compared with the historical control.• Early treatment response and gain of chromosome 8 are independent prognostic factors.Children with myeloid leukemia associated with Down syndrome (ML-DS) have superior outcome compared with non-DS patients, but suffer from higher constitutional cytotoxic drug susceptibility. We analyzed the outcome of 170 pediatric patients with ) and intrathecal central nervous system prophylaxis while omitting maintenance therapy. Still, 5-year overall survival (89% 6 3% vs 90% 6 4%; P log-rank 5 .64), event-free survival (EFS; 87% 6 3% vs 89% 6 4%; P log-rank 5 .71), and cumulative incidence of relapse/ nonresponse (CIR/NR; 6% 6 3% vs 6% 6 2%; P Gray 5 .03) did not significantly differ between the ML-DS 2006 trial and the historical control arm. Poor early treatment response (5-year EFS, 58% 6 16% vs 88% 6 3%; P log rank 5 .0008) and gain of chromosome 8 (CIR/NR, 16% 6 7% vs 3% 6 2%, P Gray 5 .02; 5-year EFS, 73% 6 8% vs 91% 6 4%, P log rank 5 .018) were identified as independent prognostic factors predicting a worse EFS. Five of 7 relapsed patients (71%) with cytogenetic data had trisomy 8. Our study reveals prognostic markers for children with ML-DS and illustrates that reducing therapy did not impair excellent outcome. The trial was registered at EudraCT as #2007-006219-2. (Blood. 2017;129(25):3314-3321)

show abstract

“…30 They are especially sensitive to cytarabine (ARA-C), possibly to the effect of the GATA1 mutations and trisomy 21 on the levels of cytarabine-metabolizing enzymes. 31 Indeed, many patients may respond favorably to a simple regimen including low-dose cytarabine, 32 An interesting clinical question, currently under study in prospective clinical trials, is whether treatment of TMD by low-dose cytarabine could prevent DS-AMKL. A related question is whether treatment of clinically silent disease, identified by molecular detection of GATA1 mutations in patients who recovered from TMD, can prevent the future development of DS-AMKL.…”

Section: Discussionmentioning

confidence: 99%

Insights into the manifestations, outcomes, and mechanisms of leukemogenesis in Down syndrome

Malinge

Izraeli

Crispino

2009

Blood

229

204

View full text Add to dashboard Cite

Children with Down syndrome (DS) show a spectrum of clinical anomalies, including cognitive impairment, cardiac malformations, and craniofacial dysmorphy. Moreover, hematologists have also noted that these children commonly show macrocytosis, abnormal platelet counts, and an increased incidence of transient myeloproliferative disease (TMD), acute megakaryocytic leukemia (AMKL), and acute lymphoid leukemia (ALL). In this review, we summarize the clinical manifestations and characteristics of these leukemias, provide an update on therapeutic strategies and patient outcomes, and discuss the most recent advances in DSleukemia research. With the increased knowledge of the way in which trisomy 21 affects hematopoiesis and the specific genetic mutations that are found in DSassociated leukemias, we are well on our way toward designing improved strategies for treating both myeloid and lymphoid malignancies in this high-risk population. (Blood. 2009;113:2619-2628) IntroductionDown syndrome (DS), or constitutional trisomy 21, is the most common human aneuploidy, with an incidence of 1 in 700 births. Nearly 80 different clinical phenotypes have been identified in people with DS, including cognitive impairment, craniofacial dysmorphy, gastrointestinal tract abnormalities, congenital heart defects, endocrine abnormalities, neuropathology leading to dementia, and immunologic defects. With respect to the hematopoietic system, children with DS frequently show macrocytosis, abnormalities in platelet counts, and an increased prevalence of leukemia. 1,2 The incidence of acute lymphoblastic leukemia (ALL; the most common leukemia in childhood) in children with DS is approximately 20-fold higher than in the general population, while the incidence of acute megakaryoblastic leukemia (AMKL) is 500-fold higher. 2 Furthermore, it has been estimated that between 4% and 10% of infants with DS are born with transient myeloproliferative disease (TMD), a clonal disease that is characterized by immature megakaryoblasts in the fetal liver and peripheral blood. 3,4 Although TMD spontaneously disappears in most cases, it is regarded as a preleukemic syndrome; approximately 20% of children diagnosed with TMD develop DS-AMKL within 4 years. The natural history of leukemia in children with DS suggests that trisomy 21 directly and functionally contributes to the malignant transformation of hematopoietic cells. It is important to note, however, that DS is not a classic genomic instability syndrome, as the overall risk of developing cancer, in particular solid tumors, is lower in these people. 5 In line with these data, experiments with a mouse model of DS showed that trisomy for orthologs of about half of the genes on chromosome 21 led to a significant reduction in the number of adenomatous polyposis coli (multiple intestinal neoplasia [APC(min)]-mediated intestinal tumors. 6 To better understand the impact of trisomy 21 on hematopoiesis, studies have been undertaken with human fetal liver cells as well as animal and cell-line models to determine the c...

show abstract

Long‐term results of an ultra low‐dose cytarabine‐based regimen for the treatment of acute megakaryoblastic leukaemia in children with Down syndrome

Abstract: 2/dose), retinylpalmitate and vincristine or standard chemotherapy. Event-free (67 ± 11%) and overall survival (77 ± 10%) at 5 years were not significantly different in both groups. Further reduction of treatment intensity in AMKL of children with DS, therefore, appears feasible.

Cited by 51 publications

References 12 publications

Infections in children with down syndrome and acute myeloid leukemia: a report from the Canadian infections in AML research group

Infections in children with down syndrome and acute myeloid leukemia: a report from the Canadian infections in AML research group

Therapy reduction in patients with Down syndrome and myeloid leukemia: the international ML-DS 2006 trial

Insights into the manifestations, outcomes, and mechanisms of leukemogenesis in Down syndrome

Contact Info

Product

Resources

About